Twist-mediated PAR1 induction is required for breast cancer progression and metastasis by inhibiting Hippo pathway
Twist-mediated PAR1 induction is required for breast cancer progression and metastasis by inhibiting Hippo pathway
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通过抑制 Hippo 通路，Twist 介导的 PAR1 诱导是乳腺癌进展和转移所必需的
DOI：
10.1038/s41419-020-2725-4
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发表时间：
2020-07-09
影响因子：
9
通讯作者：
Dong, Chenfang
中科院分区：
文献类型：
--
作者：
Wang, Yifan;Liao, Ruocen;Dong, Chenfang
乳腺癌被认为是全世界女性中最常见的癌症，转移是主要的死亡原因。蛋白水解酶激活受体1(PAR1)是参与肿瘤细胞侵袭和转移过程的GPCR家族成员。然而，PAR1在乳腺癌中的功能和潜在机制仍不清楚。在这项研究中，我们发现PAR1在高侵袭性乳腺癌细胞中高表达，并预测ER阴性和高级别乳腺癌患者的预后不良。在机制上，Twist转录诱导PAR1的表达，导致HIPPO途径的抑制和YAP/TAZ的激活；抑制PAR1抑制YAP/TAZ诱导的上皮-间充质转化(EMT)、侵袭、迁移、肿瘤干细胞(CSC)样特性、体内外肿瘤生长和转移。这些发现表明，PAR1作为Twist的直接转录靶点，可以通过控制Hippo通路促进EMT、成瘤和转移，这可能会成为治疗浸润性乳腺癌的潜在靶点。
Breast cancer is considered to be the most prevalent cancer in women worldwide, and metastasis is the primary cause of death. Protease-activated receptor 1 (PAR1) is a GPCR family member involved in the invasive and metastatic processes of cancer cells. However, the functions and underlying mechanisms of PAR1 in breast cancer remain unclear. In this study, we found that PAR1 is highly expressed in high invasive breast cancer cells, and predicts poor prognosis in ER-negative and high-grade breast cancer patients. Mechanistically, Twist transcriptionally induces PAR1 expression, leading to inhibition of Hippo pathway and activation of YAP/TAZ; Inhibition of PAR1 suppresses YAP/TAZ-induced epithelial-mesenchymal transition (EMT), invasion, migration, cancer stem cell (CSC)-like properties, tumor growth and metastasis of breast cancer cells in vitro and in vivo. These findings suggest that PAR1 acts as a direct transcriptionally target of Twist, can promote EMT, tumorigenicity and metastasis by controlling the Hippo pathway; this may lead to a potential therapeutic target for treating invasive breast cancer.